Prussian Blue Nanoparticles as Cellular T1 MRI Contrast Agents

普鲁士蓝纳米颗粒作为细胞 T1 MRI 造影剂

• 批准号: 8155168
• 负责人: SONGPING D HUANG
• 金额: $ 21.03万
• 依托单位: KENT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8155168
• 关键词: Animals; Area; Biomedical Research; Blood Circulation Time; Cell Survival; Cell membrane; Cells; Characteristics; Clinical; Contrast Media; Detection; Development; Diagnostic; Diagnostic Imaging; Dose; Drug Delivery Systems; Dyes; Engineering; Exhibits; Fibrosis; Gadolinium; Generations; Goals; Image; Impaired Renal Function; In Vitro; Injection of therapeutic agent; Ions; Iron; Ligands; Link; Magnetic Resonance Imaging; Manganese; Measures; Methods; Molecular; Particulate; Patients; Penetration; Pharmaceutical Preparations; Polymers; Positioning Attribute; Positron-Emission Tomography; Protons; Prussian blue; Radioisotopes; Relaxation; Research; Solubility; Solutions; Structure; Surface; Testing; Time; TimeLine; Toxic effect; Water; Weight; base; cancer cell; cellular imaging; cytotoxicity; design; gadolinium oxide; improved; in vivo; iron cyanide; nanoparticle; nanoparticulate; next generation; novel; quantum; single photon emission computed tomography; small molecule; surface coating; uptake

DESCRIPTION (provided by applicant): This proposal is aimed at developing Prussian blue nanoparticles (PBNPs) as a new generation of T1-weighted MRI contrast agents (CAs) with high relaxivity, long blood circulation times and ability to penetrate the cell membrane. Prussian blue (PB) is iron(III) hexacyanoferrate(II) with anidealized formula Fe4III[FeII(CN)6]3.nH2O (n=14-16) in which two different iron centers, Fe3+ (high-spin S=5/2) and Fe2+ (low-spin S=0) are bridged by the CN- groups. In the crystal structure of PB, a quarter (25%) of the FeII(CN)6 unit is absent from the crystal lattice, creating a large cavity inside the structure that is filled with water molecules. The missing FeII(CN)6 unit also causes the Fe3+ center to be coordinated by one water molecule and five CN- groups, thus giving rise to an active inner-sphere relaxation mechanism for enhancing the T1 relaxation. Due to the strong ligand-field effect and simultaneous coordination of the CN- group to both the Fe3+ and Fe2+ centers in the extended 3D network, the CN- ligand and the Fe3+/Fe2+ ions are completely locked in their lattice positions and cannot be released from the structure. As a result, PB has the lowest solubility product constant ever measured for any compound (Ksp=10-41). We have found that replacement of some of the Fe3+ ions with Mn2+ or/and Gd3+ ions in the crystal lattice can form the manganese- or gadolinium-incorporated nanoparticles, Mn@PBNPs and Gd@PBNPs with significantly increased r1 relaxivity. Besides, the structural rigidity and reduced tumbling rates of PBNPs in solution, as compared to the small molecular Gd3+-chelates, can contribute to additional T1-weighted MRI contrast enhancement in this new nanoplatform. Our goals are: (i) to explore methods for optimizing the r1 relaxivity by adjusting the nanoparticle size, level of Mn2+- or/and Gd3+-doping, and surface coating with small molecules or polymers; (ii) to systematically investigate the characteristics of cellular uptake and cellular imaging as well as potential for image-guided drug delivery applications; and (iii) to simultaneously incorporate Mn2+ or/and Gd3+ ions along with the radionuclide Ga-67 or Ga-68 for MRI-SPECT and MRI-PET bimodal imaging applications. We will endeavor to test the following four hypotheses: 1) Prussian blue nanoparticles, when properly tailored and engineered, will be effective in reducing the longitudinal relaxation time of protons from bulk water. Incorporation of Mn2+ or/and Gd3+ into this nanoplatform will significantly increase the r1 relaxivity; 2) Prussian blue nanoparticles will be internalized by cells, exhibit no toxicity and be effective in cellular imaging and in delivering small-molecular agents; 3) Prussian blue nanoparticles will be effective T1-weighted MRI contrast agents in vivo; and 4) Simultaneous incorporation of paramagnetic ions of manganese(II) or/and gadolinium(III) along with the radionuclide Ga-67 or Ga-68 into Prussian blue nanoparticles will produce effective bimodal contrast agents for in vitro and in vivo MRI-SPECT and MRI-PET imaging. Impact Our approach to exploring PBNPs as novel T1-weighted MRI is unprecedented and represents a paradigm shift in the design of new-generation CAs. The new paradigm that will emerge from this proposed research will prove to be revolutionary rather than evolutionary for increasing r1 relaxivity in a novel class of particulate T1-weighted MRI CAs, and thus will have high potential to produce a major breakthrough in MRI diagnostic imaging and may even completely change the landscape in this area of research. PUBLIC HEALTH RELEVANCE: Prussian Blue Nanoparticles as Cellular T1 MRI Contrast Agents We aim to develop novel Prussian blue nanoparticulate T1-weighted MRI contrast agents suitable for cellular imaging of cancer cells. Such agents will penetrate the cell membrane, exhibit no cytotoxicity, and can integrate imaging and delivering capabilities into a single platform for image- guided drug delivery. The design paradigm developed from this research will prove to be transformative and have potential to significantly impact the diagnostic MR imaging.

描述（由申请人提供）：该提案旨在开发普鲁士蓝纳米颗粒（PBNPs）作为新一代T1-weighted MRI造影剂（CAs），具有高弛度，长血液循环时间和穿透细胞膜的能力。普鲁士蓝（PB）是铁（III）六氰高铁酸盐（II），其理想式为Fe4III[FeII(CN)6]3。nH2O （n=14-16）中，两个不同的铁中心Fe3+（高自旋S=5/2）和Fe2+（低自旋S=0）被CN-基团桥接。在PB的晶体结构中，四分之一（25%）的FeII(CN)6单元从晶格中缺失，在结构内部形成一个充满水分子的大空腔。FeII(CN)6单元的缺失也导致Fe3+中心被1个水分子和5个CN-基团协调，从而产生了一个活跃的球内弛豫机制，增强了T1弛豫。在扩展的三维网络中，由于强配体场效应和CN-基团同时与Fe3+和Fe2+中心配位，CN-配体和Fe3+/Fe2+离子被完全锁定在它们的晶格位置，不能从结构中释放出来。因此，PB的溶解度乘积常数是所有化合物中最低的（Ksp=10-41）。我们发现，用Mn2+或/和Gd3+离子取代晶格中的一些Fe3+离子可以形成锰或钆结合的纳米粒子Mn@PBNPs和Gd@PBNPs，其r1弛豫率显著增加。此外，与小分子Gd3+螯合物相比，PBNPs在溶液中的结构刚性和降低的翻转速率可以在这种新的纳米平台中增加t1加权MRI对比增强。我们的目标是：(i)探索通过调整纳米颗粒尺寸、Mn2+-或/和Gd3+掺杂水平以及小分子或聚合物表面涂层来优化r1弛度的方法；（ii）系统地研究细胞摄取和细胞成像的特征，以及图像引导药物输送应用的潜力；（iii）同时加入Mn2+或/和Gd3+离子以及放射性核素Ga-67或Ga-68，用于MRI-SPECT和MRI-PET双峰成像应用。